Kinases are essential cellular signaling molecules. Mutations in kinases can lead to diseases or conditions including immunodeficiencies, cancers, cardiovascular diseases and endocrine disorders, such as Parkinson's disease, metabolic diseases, tumorigenesis, Alzheimer's disease, heart disease, diabetes, neurodegeneration, inflammation, kidney disease, atherosclerosis and airway disease.
Cancers result from deregulated signaling pathways that mediate cell growth and programmed cell death (apoptosis). Protein kinases are a large family of proteins that play an important role in signaling pathways that regulate a number of different cellular functions, such as cell growth, differentiation, and death (e.g., Kumar et al., Expert Opin. Emerging Drugs (2001) 6(2) pp. 1-13; U.S. Pat. Publ. No. 2003/0199511, WO 2004/030671, WO 2004/094386, WO 2004/096130, WO 2004/041162, WO 2004/022562, WO 2004/048343, and references cited therein). Protein kinases include those classified as tyrosine, serine/threonine (e.g., Akt or PKB), or dual specific, based on acceptor residue. Protein tyrosine kinases include intracellular domains of transmembrane growth factor receptors such as EGF receptor (EGFR), PDGF receptor (PDGFR), VEGF receptor (VEGFR), and FGF receptor (FGFR), and cytosolic kinases such as src, abl, and lck. Serine/threonine kinases include, for example, MAP kinase, MAPK kinase (MEK), Akt/PKB, Jun kinase (JNK), CDKs, protein kinase A (PKA) and protein kinase C (PKC).
Hyperactivity of protein kinases is implicated in a variety of human cancers. For example, the Akt2 kinase has been found to be over-expressed in ovarian tumors (J. Q. Cheung et al., Proc. Natl. Acad. Sci. U.S.A. 89: 9267-9271 (1992)) and pancreatic cancers (J. Q. Cheung et al., Proc. Natl. Acad. Sci. U.S.A. 93: 3636-3641 (1996)), and the Akt3 kinase was found to be over-expressed in breast and prostate cancer cell lines (Nakatani et al., J. Biol. Chem. 274: 21528-21532 (1999)).
Various protein kinase inhibitors have been shown to effectively treat certain cancers. For example, Gleevec™ (imantinib, Novartis), can be used to treat chronic myeloid leukemia (CML) (Kumar et al.), flavopiridol (Aventis) has been evaluated for treating mantle cell lymphoma and fludar refractory chronic lymphocytic leukemia, and a Raf kinase inhibitor (BAY-43-9006) has been evaluated for treating solid tumors and myeloid leukemia (WO 2004/022562).
Thus, drugs targeted against protein kinases represent a new generation of chemotherapy agents directed toward specific molecular targets, and thus have the potential for greater efficacy in treating various cancers, with fewer side effects than conventional chemotherapeutic agents.
Various pharmaceutically active [1,2,4]triazines are known. For example, U.S. Pat. No. 4,560,687 and U.S. Pat. No. 4,311,701 provide 3,5-diamino-6-aryl-[1,2,4]triazines useful for treating CNS disorders; EP 0021121 provides 3-amino-6-aryl-[1,2,4]triazines useful for treating CNS disorders; U.S. Pat. No. 4,190,725 provides anti-inflammatory 5,6-diaryl-[1,2,4]triazines; U.S. Pat. No. 3,948,894 provides anti-inflammatory 3-amino-5,6-diaryl-[1,2,4]triazines; U.S. 2004/0102436 provides various 2-amino-5,6-diaryl-[1,2,4]triazine PGI2 receptor agonists; WO 00/66568 provides various 3-aryl-[1,2,4]triazine pesticides; WO 2004/074266 provides various 3-phenylamino- or 3-halo-[1,2,4]triazine HIV replication inhibitors; WO 97/20827 provides various 3,5-diamino-6-fluorophenyl-[1,2,4]triazine as inhibitors of glutamate release from the central nervous system; U.S. Pat. No. 4,649,139 provides 3,5-diamino-6-aryl-[1,2,4]triazines useful as cardiovascular agents; WO 2004/096129 provides 5,6-diaryl-[1,2,4]triazines useful for inhibiting Akt; U.S. Pat. No. 6,159,974 and WO 98/42686 provide 3-pyridyl-6-aryl-[1,2,4]triazine LDL receptor gene expression promoters; WO 03/077921 provides various 5-amino-[1,2,4]triazines useful as protein kinase inhibitors; EP 0088593 and U.S. Pat. No. 4,585,861 provide various 3-heterocyclo-5,6-diaryl-[1,2,4]triazines useful as activators of gamma-aminobutyric acid and benzodiazepine binding in the central nervous system; DD 248363 provides ampicillin derivatives having a 1,2,4-triazinyl moiety; GB 759014 describes improved methods of preparing 3,5-diamino-6-aryl-[1,2,4]triazines; Abdel-Rahman et al., Bollettino Chimico Farmaceutico (1999), 138(4), 176-185, describe the synthesis of (triazinyl)triazines; Dinakaran et al., Biological & Pharmaceutical Bulletin (2003), 26(9), 1278-1282, describe the synthesis of 3-quinazolinone-[1,2,4]triazines; Heinisch, Journal fuer Praktische Chemie (Leipzig) (1969), 311(3), 438-444 describe the synthesis of morpholine-[1,2,4]triazines; Yoneda et al., Chemical & Pharmaceutical Bulletin (1978), 26(10), 3154-3160, describe the synthesis of 3-aryl-5,6-diamino-[1,2,4]triazines; Yondea et al., Chemical & Pharmaceutical Bulletin (1973), 21(5), 926-930, describe the synthesis of [1,2,4]triazine-6-carbothioamides; Li et al., Huaxue Xuebao (1980), 38(6), 581-583 describe 3-substituted-5-hydroxy-6-methyl-[1,2,4]triazines; Neunhoeffer et al., Liebigs Annalen der Chemie (1990), (7), 631-640 describe 3-pyridyl-5-alkynyloxy-[1,2,4]triazines; Pochat, Tetrahedron Letters (1981), 22(37), 3595-3596 describes 3,6-diaryl-5-hydroxy-[1,2,4]triazines; Heinisch, Journal fuer Praktische Chemie (Leipzig) (1987), 329(2), 290-300 describes [1,2,4]triazine-6-carboxylic acids; Li, J. Org. Chem. (1993), 58, 516-519 describes pyrrolyl [1,2,4]triazines; Paudler et al., J. Org. Chem. (1966), 31, 1720-1722 describe the synthesis of various [1,2,4]triazines; Benson et al., J. Org. Chem., (1992), 57, 5285-5287 describe intramolecular cycloadditions of indole and [1,2,4]triazine; and Limanto et al., Organic Letters (2003), 5(13), 2271-2274 describe 5-substituted-3-amino-1,2,4,-triazines. The triazines of the above references all have structures which differ substantially from the compounds of the present invention, described below.
U.S. 2003/0199511 and U.S. 2004/0127538 describe various indazoles which lack the [1,2,4]triazine ring of the compounds of the present invention, described below.